A new bioinformatics study provides insights into the origin of the genetic code. Learn more...

How did the genetic code—DNA and RNA bases that assign a specific amino acid
sequence to proteins—come into being? Numerous theories, all unproven,
attempt to explain this mystery. Proposed in the mid-1960s by Carl Woese,
the “stereochemical hypothesis” maintains that the code evolved as a result
of RNA coming into direct contact with the amino acids it codes for. Another
theory, proposed by Francis Crick, is that the code evolved from the last
common universal ancestor and is an accident frozen in time.

A new bioinformatics study published in the October issue of Nucleic Acids
Research suggests that messenger RNAs (mRNAs) and the proteins they
code for bind to each other in a complementary fashion—a finding that
furthers the stereochemical hypothesis, according to the study authors.[1]

“What we hope our results will now do is reignite this discussion with a clear
bias in the direction of the complementary stereochemical hypothesis by
Woese,” noted senior author Bojan
Zagrovic, a group leader at the Max F. Perutz Laboratories at the
University of Vienna in Austria.

In recent years, researchers have found examples of mRNA-protein interactions
involving metabolic enzymes and transcription factors, as well as other
proteins that were not previously expected to bind mRNAs. A handful of
proteins—such as thymidylate synthase, dihydrofolate reductase and p53—are
known to bind to their cognate mRNAs, although the significance of these
interactions is still unclear.

In the study, Zagrovic and postdoctoral researcher Anton Polyansky analyzed
the interfaces between RNA and protein, for which 299 three-dimensional
structures were available in the Protein
Data Bank. They used a predetermined distance cutoff of 8 ångströms or
less to identify RNA bases and amino acids that come into close contact and
from this derived the preferences of the 20 natural amino acids for the 4
RNA bases.

At protein-RNA interfaces, amino acids tend to contact nucleotide bases that
correspond with their own codons. The group also found a high level of
matching between mRNA composition and corresponding amino acid stretches,
especially those encoded by purines, when they analyzed the human proteome
and the coding sequences of corresponding mRNAs from UniProtKB.

There are many scenarios where contact between mRNA and its protein could have
functional significance, said Zagrovic. For some proteins, it could provide
a means of translational control. “There’s a long list of proteins that do
it,” he said. “It’s just that the physicochemical principles have not been
elucidated.” In addition, the interactions could play a role in virus
assembly, or in the making of P bodies, membrane-less compartments within
cells that are rich with proteins and RNA.

The new study suggests that proteins bind their mRNAs, but the interactions
might not be specific, the authors noted. “The biggest next frontier is
trying to test some of these ideas experimentally,” said Zagrovic. “The
question is, will a protein bind to its own mRNA?” The group plans to start
with purified mRNA and protein before moving into cells. They also plan to
examine whether unrelated mRNAs match up to a protein as well as cognate
mRNAs do.

“Now with Bojan Zagrovic’s reopening of the debate, new ways of thinking are
necessary and Carl Woese’s hypothesis is back on the agenda. The genetic
code is for sure frozen but probably not accidentally,” said Renée
Schroeder, a colleague at Max F. Perutz Laboratories in University of Vienna
who was not involved with the study but is acknowledged in the paper. “Let’s
see where Zagrovic’s research will take him.”